Abstract A better understanding of the causes, epidemiology, and risk factors of infectious causes of acute febrile illnesses (AFI) is a global health priority, particularly for Central America and the Caribbean. AFI syndromes have overlapping clinical features that make clinical diagnoses challenging and, without advanced laboratory facilities that rarely are available in Central America, the epidemiology of these pathogens is largely unknown. In order to ensure that limited public health resources are used efficiently, we need to assure that accurate and up-to-date data and information are available for targeted and precise interventions. Our innovative project, Reducing the morbidity and mortality due to acute febrile illnesses in Central America and the Dominican Republic, will address this information gap on AFIs in the Dominican Republic and Guatemala--two large and strategically important countries in the Caribbean and Central America, respectively. The specific aims are to: AIM 1: Determine the risk factors and environmental/sociodemographic drivers of transmission for common AFI pathogens in the Dominican Republic and Guatemala. AIM 2: Determine the transmission dynamics and proportionate morbidity serious causes of AFI syndromes in the Dominican Republic and Guatemala. AIM 3: Identify emerging and poorly characterized causes of AFI in the Dominican Republic and Guatemala. For this project, we will conduct two field-activities and three supporting activities: (1) national, population- representative cross-sectional serological surveys enrolling 6000 healthy children and adults in the Dominican Republic and Guatemala to detect associations between pathogen serostatus and individuals, environmental and population-level covariates; (2) prospective sentinel AFI surveillance at two hospitals in each country to provide data on the morbidity and chronicity of infection of the target pathogens; (3) data analysis and transmission dynamic modelling using serological and surveillance outputs to characterize risk factors at different ecological scales, and transmission dynamics and proportionate morbidity of target pathogens; (4) decision support tools using outputs from the data analysis and modelling to improve the precision of control interventions; and (5) data sharing and publication of the project outputs. Study findings and products from this project will allow health ministries to target public health interventions, thereby increasing effectiveness and assuring limited resources are maximized. The project will also provide an innovative prototype for how regional and global health authorities can leverage mixed data sources and novel analytics to achieve Precision Public Health interventions.